Diabetes
mellitus is one of the civilization diseases with rapidly increasing frequency of occurrence around the world,
especially among populations of highly developed countries. In Poland, for example, there are about 2.5 million registered
diabetics. Diabetic neuropathy
is one of late complications of this disease and
it is the most common type of neuropathic pain resulting from nerve damage, and often persisting after healing.
However, its mechanism is not fully understood. Classical
pathomechanisms of diabetic neuropathy development – being the consequence of high
blood glucose levels (hyperglycemia) – are microvascular disturbances in nerves
(observed in 50% of patients with chronic diabetes mellitus), and increase in
sorbitol accumulation due to excessive glucose metabolism leading to a destruction
of nerve fibers sheath.

However, many research centers are focusing their attention on the
participation of cytokines in the processes responsible for the development of
neuropathy. Cytokines are proteins with a very broad scope of action. This
group consists not only of interleukins or TNF superfamilies members, but also
chemokines – small molecules with well-established chemoattractant properties (i.e.
inducing cell migration in areas of their secretion). Nevertheless, current
studies indicate that chemokines are crucial in the development of neuropathic
pain, including diabetic neuropathy.

The most
common model used in studies on diabetic neuropathy development is a mice streptozotocin (STZ)
model. Streptozotocin is a substance which,
when administrated intraperitoneally, destroys
beta cells (responsible for insulin secretion)
in the pancreas leading to hyperglycemia. Our research [1] performed on mice
streptozotocin model of diabetic neuropathy showed the activation of microglia
(resident macrophage of the central nervous system) and increase of XCL1 and
XCR1 protein level parallel with the development of neuropathic pain symptoms. Minocycline,
on the other hand, a substance whose multidirectional mechanism of action has
analgesic properties, not only prevents microglial activation, but also
inhibits the increase in XCL1 and XCR1 levels, as reflected in a subsequent
onset of neuropathic pain symptoms. This correlation raised the question of the
actual contribution of XCL1 in the development of neuropathic pain with the
participation of microglial cells. The response obtained after intrathecal
administration of exogenous XCL1 to control animals confirmed that the concentration
of XCL1 higher than homeostatic causes activation of microglia, and
consequently, the appearance of neuropathic pain symptoms. This dependence was
completed with the neuronal location of XCR1, which turned out to be crucial
for rapid pronociceptive (acute pain) response observed after XCL1 administration.
This neuronal stimulation due to the increase in XCL1 levels seems to result in
the release of numerous pronociceptive factors activating microglial cells and leading
to the development of pain symptoms.

The
treatment of neuropathic pain, also the one associated
with diabetes, is extremely difficult due to the loss of efficacy after long-term use of opioid analgesics (such
as morphine). This forces researchers and clinicians to continually seek a more
effective treatment regimen. The use of neutralizing antibodies for selected
cytokines seems to be a promising avenue. Studies conducted in the
streptozotocin model of diabetic neuropathy demonstrated that XCL1 neutralizing
antibody not only affects the alleviation of already developed pain symptoms,
but also prevents microglial activation induced by exogenous XCL1. These are pivotal
results, since they indicate the possibility of using substances which act as
potential analgesics not only on microglial cells (i.e. minocycline) but also on endogenous cytokines (i.e. neutralizing
antibodies).